Item Details

title

Diurnal Rhythms in Striatal Dopamine and Acetylcholine Signaling in a Rodent Model of Cocaine Use Disorder

author

Iacino, Melody Courtney-Lynn

abstract

Endogenous circadian rhythms are ubiquitous in nature and essential to life. Circadian misalignment increases the risk of developing a psychiatric illness, including cocaine use disorder (CUD). The mesolimbic dopamine (DA) system, including the nucleus accumbens core (NAcc), is an important regulator of the motivated and reward-associated behaviors that underlie CUD. Moreover, acetylcholine (ACh) from striatal cholinergic interneurons (CINs) directly influences DA release within this system, thus implicating CIN ACh in mediating CUD-associated reward. Although diurnal rhythms have been documented in both drug-taking and DA dynamics, the bidirectional relationship between DA and ACh systems affecting diurnal rhythms based on drug history remains unclear. Thus, this dissertation aimed to characterize diurnal rhythms in baseline DA dynamics and local modulators of DA release by cocaine access pattern [i.e., Long continuous access (LgA), short continuous access (ShA), and intermittent access (IntA)]. We first used ex vivo fast-scan cyclic voltammetry (FSCV) to evaluate the effects of cocaine access pattern on diurnal DA dynamics. Aside from baseline DA release magnitude, this study also characterized the effects of cocaine access pattern on initial probability of DA release using paired-pulse ratios (PPRs). We demonstrated that the cocaine intake pattern disrupts naïve DA rhythms differently depending on the stimulation frequency. Next, we examined the effects of cocaine access pattern on diurnal rhythms in cholinergic modulation of NAcc DA dynamics using ex vivo FSCV and cell-attached patch-clamp electrophysiology. We showed that CIN ACh activity was higher mid-light cycle (ZT6) than mid-dark cycle (ZT18) and that cholinergic modulation of NAcc DA release was differentially affected by cocaine access pattern. Finally, we assessed the effects of cocaine access pattern on D2-like receptor (D2R) and D2-autoreceptor (D2AR) sensitivity to inhibiting DA release across time-of-day using ex vivo FSCV. We demonstrated that diurnal rhythms in D2R versus D2AR sensitivity to inhibiting DA were differentially affected by cocaine access pattern and stimulation frequency. Overall, this dissertation served to characterize diurnal NAcc DA rhythms as influenced by cocaine intake pattern and pinpointed CINs and specific receptor systems, including D2Rs, as a potential novel mechanistic target for restoring cocaine-induced diurnal disruptions in the treatment of CUD.

subject

Acetylcholine

Cholinergic interneuron

Circadian rhythm

Cocaine use disorder

Diurnal rhythm

Dopamine

contributor

Ferris, Mark J (advisor)

Gould, Robert W (committee member)

Centanni, Samuel W (committee member)

Macauley, Shannon L (committee member)

date

2025-06-24T08:36:23Z (accessioned)

2025 (issued)

degree

Physiology and Pharmacology (discipline)

embargo

2025-12-23 (terms)

2025-12-23 (liftdate)

identifier

http://hdl.handle.net/10339/110996 (uri)

language

en (iso)

publisher

Wake Forest University

type

Dissertation